Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat.

Jesus Prieto-Lloret,Philip I Aaronson,Elena Olea,Inmaculada Docio,Ana Obeso,Asuncion Rocher,Angela Gomez-Niño,Ana Gordillo-Cano

doi:10.3390/antiox11010054

Abstract

Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increased hematocrit, weight loss, and an increase in pulmonary artery pressure (PAP), compared to CIH, CSH seems to have more of an effect on the pulmonary circulation, whereas the effects of CIH are apparently more targeted on the systemic circulation. The results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols are not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and, therefore, the increase in PAP that results from CIH.

Highlights

To compare the effect of sustained vs. intermittent hypoxia on the physiological responses to chronic hypoxia, 3-month-old male rats were exposed to 10% O2 continually or 5–21% O2 (8 h/day) for 2 weeks
There was a significant difference with respect to the development of polycythemia: the rats exposed to Chronic sustained hypoxia (CSH) but not chronic intermittent hypoxia (CIH) developed significant polycythemia and increased blood hemoglobin levels compared with normoxic rats
It is noteworthy that our results differ in some ways from those reported previously, and it seems most likely that this is due to the methodological variability between different studies, for example, in the addition of CO2 to the hypoxic gas mixture [34], the overall duration of the hypoxic interventions, and the timing of the oscillations of pO2 imposed during CIH

Summary

Introduction

Pulmonary and systemic hypoxemia, sustained or intermittent over time, triggers homeostatic responses that tend to restore normal levels of oxygen, as well as pathological processes caused by adverse tissue adjustments. Chronic sustained hypoxia (CSH), resulting from habitation at a high altitude or from respiratory disorders (i.e., COPD), initiates physiological adaptations that include the activation of carotid body (CB), eliciting hyperventilation; an increase in red blood cell production, which improves the O2 carrying capacity; angiogenesis to facilitate the blood flow and oxygen transport to the tissues; and cell metabolic re-programming, which reduces O2 consumption [1,2]. Antioxidants 2022, 11, 54 may have deleterious effects over time, such as a prolonged activation of hypoxic pulmonary vasoconstriction (HPV), pulmonary hypertension (PH), right ventricular hypertrophy, and heart failure [3]. Chronic alveolar hypoxia is the cause of Group Three PH (WHO classification) and acts by inducing vasoconstriction as well as by stimulating the remodeling of small pulmonary arteries [4,5]

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